A new study from USC suggests enhancer sequences, which regulate gene expression, may play a key role driving prostate cancer. These findings point to possible new drug targets.

The study, just published in Genome Biology, could help with the development of targeted cancer therapies. The corresponding author of the study is Suhn Kyong Rhie, PhD, assistant professor of cancer biology at the Keck School of Medicine of USC.

“More importantly, our study is the first to show that enhancers are organized in a hierarchy,” Rhie said. “Some enhancers function as ‘master switches,’ controlling the activity of many other enhancers and cancer-promoting genes, while others play more supportive or compensatory roles.”

Enhancers are part of interconnected 3D networks. Some of these networks serve as central hubs, controlling multiple cancer-related genes. This team seems to have found one of these.

They used advanced 3D genome mapping technology and a large data set of prostate samples.

The Keck researchers, at University of Southern California (USC), uncovered a 3D interconnected network of DNA enhancers that exists only in prostate cancer cells, not normal cells.

Enhancers are part of what was initially dubbed “junk” DNA, because it does not code for proteins. This type of DNA is now being studied much more closely to uncover its other biological effects, as it’s been found to help control gene expression, shape chromosomes, and guide cell growth, among other things.

Enhancers can play a critical role in cancer and other diseases, but there are still questions about how they work together to control gene expression. They are already the target of one approved drug, Casgevy, a gene editing drug for sickle-cell anemia.

Casgevy treats sickle cell disease and transfusion-dependent ?-thalassemia by targeting an enhancer to alter gene expression. This Keck study could lead to a similar approach to treating prostate cancer or other diseases.

An enhancer is a short region of non-coding DNA, 50 to 1,500 base pairs long, that increases a gene’s transcription rate. Enhancers can be upstream, downstream, within introns, or far away from the target gene. They can be close or thousands of base pairs away from the gene they help regulate.

Analyzing 201 datasets from both prostate tumor samples and healthy prostate tissue, the Keck researchers identified more than 3,000 prostate cancer-specific DNA enhancers.

Rhie’s lab focuses on chromatin interactions, which investigates how DNA folds and interacts to regulate gene expression. Using 201 datasets from both prostate tumor samples and healthy prostate tissue, her team identified 3,216 key enhancers specific to prostate cancer.

They then zoomed in on one region of the genome and used Region Capture Micro-C to map physical interactions between enhancers and genes at extremely high resolution. They found that in prostate cancer cells, enhancers formed an interconnected 3D network that did not exist in normal prostate cells.

Next, they used CRISPR to delete enhancers one at a time and observe how this affected enhancer activity, chromatin interactions, gene expression and cancer cell growth.

They found that not all enhancers were equivalent. Deleting some enhancers had little effect. Deleting other “central” enhancers disrupted the entire network, reducing the activity of other enhancers, switching off many cancer-promoting genes and slowing cancer.

The team said the findings also deepen understanding of “non-coding” or “junk” DNA, which makes up most of the genome.

“What we’ve shown for the first time is that there is a hierarchy of enhancers—some act as master switches, playing a central role in regulating many enhancers and genes, while others are more compensatory,” said Rhie.

“We think these findings will apply to many other cells, tissues, and diseases. At this point, it’s basic science that shows the complexity of how the genome works, but it also has the potential to inform future therapies.”

Based on these findings and others, gene-editing therapies could one day edit these master switches to control multiple cancer-promoting genes at the same time.

“But there are still important questions to answer before this approach can be translated into new therapies, including the potential side effects of targeting the wrong enhancer,” Rhie said.

Her lab is now studying how enhancer activity plays a role in resistance to existing cancer therapies. They are also working to understand how various enhancers work together in other types of cancer.